Prostate cancer may cause pain, difficulty in urinating, erectile dysfunction and other symptoms. However, many men who develop prostate cancer never have symptoms, undergo no therapy, and eventually die of other causes. The walnut-shaped prostate gland surrounds part of the channel that drains the bladder. When enlarged or cancerous it may compress the channel, obstructing the free flow of urine. While the gland's exact function is not fully understood it is susceptible to three common diseases: prostatitis (infection of the prostate), enlargement, called benign prostatic hyperplasia, and cancer. Prostate cancer is a silent disease and often there are no symptoms for months or years, or until the disease has spread. Consequently, about one-half of the cases are discovered only when the cancer has spread to other parts of the body. What could have been curable in an early stage then becomes life-threatening.
The development of prostate cancer may be linked to increased levels of certain hormones. High levels of androgens (male hormones, such as testosterone) promote prostate cell growth, and may contribute to prostate cancer risk in some men. Some researchers have noted that men with high levels of another hormone, insulin-like growth factor-1 (IGF-1), are more likely to get prostate cancer. IGF-1 hormone is similar to insulin, but it works on cell growth, not sugar metabolism. Some recent studies have found that inflammation may contribute to prostate cancer by increasing DNA damage. Inherited DNA changes in certain genes may cause about 5% to 10% of prostate cancers.
Prostate cancer can often be found early by testing the amount of prostate-specific antigen (PSA) in the blood. Prostate cancer may also be found on a digital rectal exam (DRE). Neither the PSA test nor the DRE is 100% accurate. If certain symptoms or the results of early detection tests—the PSA blood test and/or DRE—suggest that you might have prostate cancer, the doctor will do a prostate biopsy to find out if the disease is present.
Prostate cancer can be treated with surveillance, surgery, radiation, chemo-, cryo- and hormonal therapy. Side effects are common and include urinary incontinence and erectile dysfunction. About 90% of men who have had orchiectomy (surgical removal of the testes) have reduced or absent libido (sexual desire) and impotence. Men getting this treatment should be watched and treated for osteoporosis to help prevent broken bones. Some men also experience hot flashes (these may go away with time), breast tenderness and growth of breast tissue, anemia (low red blood cell counts), decreased mental acuity (sharpness), loss of muscle mass, weight gain, fatigue, decrease in HDL (“good”) cholesterol and depression.
Androgens, produced mainly in the testicles, stimulate prostate cancer cells to grow. Lowering androgen levels (androgen deprivation therapy, ADT) often makes prostate cancers shrink or grow more slowly. In advanced prostate cancer, however, the prostate eventually becomes insensitive to the hormonal treatment. The tumour grows back and is untreatable. When the tumour becomes androgen-independent, other factors such as insulin-like growth factor will act to stimulate the androgen receptor (AR). Currently there is no consensus as to whether it is best to start ADT early or try to delay it (to delay developing androgen resistance); whether to use continuous or intermittent ADT; or whether to combine several agents or methods to block androgen.
The AR (located on chromosome Xq11-12) is a steroid receptor whose main function is to bind to DNA to regulate gene expression. One of the known target genes of AR activation is insulin-like growth factor I (IGF-1). Although the AR is a nuclear receptor, it is located in the cytosol until activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone. The binding of an androgen to the AR results in a conformational change in the receptor which in turn causes dissociation of heat shock proteins, dimerization, and transport from the cytosol to the cell nucleus where the AR dimer binds to a specific sequence of DNA known as a hormone response element.
The AR is most closely related to the progesterone receptor, and progestins in higher dosages can block the AR. The AR contains common functional domain structures, including an N-terminal domain (NTD) that harbours activation function 1 (AF1), a central DNA binding domain (DBD) and a C-terminal ligand binding domain (LBD) that contains activation function 2 (AF2). The AF2 of the AR-LBD, formed by helices 3, 3′, 4 and 12, is a highly conserved hydrophobic surface that is stabilized by ligand-binding and required for co activator recruitment.
Established coactivators of AR that can regulate receptor hormone-binding prior to nuclear translocation include ARA70 and the hsp90 chaperone protein. While hsp90 has been shown to maintain AR in a high affinity ligand-binding conformation, ARA70 has been suggested to change the conformation of cytosolic AR so that it binds and/or retains androgen more easily and also translocates to the nucleus at a faster rate. Moreover, ARA70 was shown to specifically retard the dissociation of steroid hormones, like estrogen (17 beta-estradiol), which is also known to enhance AR activity, without affecting association of hormone with the receptor.
AR mediates transcriptional activation predominantly through its N-terminal domain AF1 and C-terminal LBD AF2 activation functions. The highly conserved AF2 hydrophobic surface in the LBD of AR is stabilized by androgen and required for recruitment of certain coactivators (namely SRC/p160). Binding of androgen to AR is thought to stabilize helix 12 of AF2 to complete the coactivator binding surface, allowing their recruitment and leading to enhanced AR transcription.
Dopa decarboxylase (DDC) is an enzyme that catalyses decarboxylation of L-3,4-dihydroxyphenylalanine (L-dopa or levodopa) into dopamine (DA) and 5-hydroxytryptophan (5-HTP) into serotonin (5-HT). DDC is not the rate-limiting step in the synthesis of dopamine and serotonin. However, it becomes the rate-limiting step of dopamine synthesis in patients treated with L-DOPA (such as in Parkinson's Disease), and the rate-limiting step of serotonin synthesis in people treated with 5-HTPagonists and the like (such as in mild depression or dysthymia).
Catalytic activity of DDC is dependent on the pyridoxal 5′-phosphate (PLP) cofactor molecule, which binds DDC at Lys residue 303 and allows decarboxylation of amino acid substrates through a Schiff base mechanism. In this reaction, CO2 is released from the amino acid substrate α-carbon and the same carbon is protonated to form the amine product. Mutational analysis performed on DDC has highlighted the importance of numerous residues for enzymatic activity, with one of the most essential residues being Lys303. Using the above mechanism, DDC catalyzes the synthesis of DA and 5-HT but has been suggested to also synthesize trace amines from other amino acids, such as tyrosine, phenylalanine and tryptophan.
The cell surface G-protein-coupled receptors (GPCRs) for DA and 5-HT are known to modulate a plethora of signal transduction pathways. The five DA receptor subtypes (D1 through D5) have been grouped into two classes, the D1-like and D2-like receptors. DA activation of the D1-like receptors, D1 and D5, stimulates adenylyl cyclase activity, elevation of intracellular cAMP and PKA activation. Activation of D2-like receptors, D2, D3 and D4, mediate inhibition of adenylyl cyclase, reduction of cAMP and inhibition of PKA. MAPK and Akt are also possible downstream effectors of both D1- and D2-like DA receptor stimulation. Serotonin receptors have been divided into seven subfamilies by convention. These include 5-HT1 through 5-HT7 GPCRs, except for 5-HT3 receptors, which are serotonin-gated ion channels. 5-HT GPCRs can modulate PKA, PKC, MAPK, PI3-kinase and many other signal transduction pathways.